Renoprotective effects of incretin‐based drugs: A novel pleiotropic effect of dipeptidyl peptidase‐4 inhibitor

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide, and is a serious problem that must be addressed. Incretin-based drugs stimulate insulin secretion from pancreatic b-cells blood glucose-dependently with low risk for hypoglycemia and bodyweight gain. In addition, incretin acts on the multiple organs through the incretin receptors as well as the pancreas. Several reports showed the effects of incretin on the kidneys including anti-inflammation, antioxidative stress, anti-apoptosis and the decrease in sodium reabsorption, which could explain in part the antihypertensive action. These effects might be related to preventing progression of diabetic nephropathy. Recently, two types of incretin-based drugs have been developed; glucagon-like peptide 1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor. GLP-1 receptor agonist decreases the blood glucose level by stimulating insulin secretion and decreasing glucagon secretion through the GLP-1 receptor on the islet cells. GLP-1 receptor agonist might also act on many organs through a GLP1 receptor other than the pancreas. In contrast, DPP-4 inhibitor not only elevates the endogenous incretin level in the blood, but also affects the pathways independent of the incretin receptors. DPP-4 could promote degradation of several molecules including chemokines and cytokines, as well as DPP-4. Furthermore, DPP-4 is known to be expressed on the cell membrane of many types of cells including immune cells (Figure 1). Therefore, DPP-4 inhibitor and GLP-1 receptor agonist are in fact different drugs, although these drugs are included in the same category. In previous studies using GLP-1 receptor agonist or DPP-4 inhibitor, the mechanism of the renal protective effect of incretin is mainly mediated through the GLP-1 receptor. Some reports showed that the renal protection of DPP4 inhibitor contributed in part to several substrates influenced by DPP-4 enzyme activity, including stromal-derived factor1a (SDF-1a). To our knowledge, there has been no report of the renoprotection by DPP-4 inhibitor through the direct action on DPP-4 per se or on DPP-4 expression in the kidney. Interestingly, Kanasaki et al. recently published an article that showed that DPP-4 inhibitor prevented kidney fibrosis through DPP-4 itself, entitled ‘Linagliptin-mediated DPP4 inhibitor ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen’ in Diabetes in June 2014. Kanasaki et al. used a fibrotic diabetic kidney disease model – streptozotocininduced diabetes in CD-1 mice. Diabetic mice showed severe fibrosis, increased DPP-4 protein levels in the glomerular basement membrane, tubules and peritubular vascular cells, and increased DPP-4 enzyme activity at 24 weeks after the initiation of diabetes. Mice were treated with linagliptin for 4 weeks at 20 weeks after the onset of diabetes, which improved kidney fibrosis associated with the endothelial-to-mesenchymal transition (EndMT), and DPP-4 activity/protein expression through microribonucleic acid (miR)-29s restoration. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic process, as assessed by messenger ribonucleic acid microarray analysis. In diabetic nephropathy, transforming growth factor (TGF)b plays a central role in renal fibrosis and also induces EndMT, which is considered as a part of diverse sources in kidney fibrosis. They examined the profibrotic molecules mechanism by using cultured endothelial cells to evaluate the relationship between DPP-4 and EndMT, and the contribution to miR-29s. As a result, they showed that linagliptin inhibited the TGF-b2-induced DPP-4 expression and EndMT by blocking Smad3 phosphorylation. The expression of DPP4 was elevated by downregulation of miR-29s by using antagonists of miR-29s or inhibitors, and reduced by upregulation of miR-29s by mimetic miR-29s transfection. These data show that miR29s regulates the DPP-4 expression. DPP-4 is expressed on the cell surface in the liver, kidney, intestine and immune cells, such as lymphocytes and macrophages. Independent of serine protease enzymatic activity, DPP-4 interacts with extracellular matrix components and regulates cell–cell and cell–extracellular matrix interactions. Through these functions, DPP-4 regulates diverse biological processes, including cell differentiation, adhesion, immune modulation, apoptosis and neoplastic transformation. In the previous reports, DPP-4 inhibitor suppressed cardiac fibrosis in the 5/6nephrectomy-indiced chronic renal failure model, and attenuated hepatic fibrosis in porcine serum-induced liver fibrosis model. In their study, diabetic mice treated with DPP-4 inhibitor showed a signifi*Corresponding author. Kenichi Shikata Tel.: +81-86-235-6508 Fax: +81-86-235-6510 E-mail address: [email protected] Received 14 May 2015; revised 19 May 2015; accepted 19 May 2015